Project Summary/Abstract Cancer immunotherapy holds tremendous promise as a strategy for eradicating solid tumors. However, a poor T cell infiltration and persistence within the tumor microenvironment severely limits the accessibility of most immunotherapies to a broad patient population. There is an increasing demand for therapeutic platforms that boost the immunogenicity of tumors while curbing the onset of adaptive resistance mechanisms. This proposal sets forth a strategy for achieving this using allied approaches enabled by focused ultrasound (FUS) and synthetic nano-cancer vaccines. It is hypothesized that focused ultrasound (FUS) - a technique for non- invasive, non-ionizing perturbation of tumors using precisely targeted acoustic waves - can serve as an ?auto- vaccination? strategy in solid tumors. During the F99 phase of this award, I propose to (i) ascertain the mechanisms by which spontaneous immunity against primary or disseminated tumors is elicited by FUS and (ii) apply this information to design and test immunotherapeutic approaches predicted to synergize with FUS. These studies will be performed across models of brain metastatic melanoma, glioma, and breast cancer. This framework is designed to permit insight into the distinct contributions of the brain and peripheral microenvironments to elicitation of anti-tumor immune responses with FUS. Our institution is well-positioned to conduct and translate FUS immune modulation research owing to the resources and strengths offered by its Focused Ultrasound Center and Human Immune Therapy Center. A significant capacity for bench-to-bedside translation is evidenced in this proposal, as pre-clinical findings in breast cancer will be benchmarked to human biopsies generated from an ongoing ?first-in-human? clinical trial at University of Virginia (UVa) that combines FUS ablation with checkpoint blockade in metastatic breast cancer. I will complete this research under the mentorship of Dr. Richard Price (UVa Biomedical Engineering), whose lab boasts a strong history of research in the effective deployment of focused ultrasound for targeted drug and gene delivery to the brain. The F99 phase of this award aligns with the remaining 2 years of my tenure in the PhD program in Biomedical Engineering at UVa. In the K00 phase of this award, I will identify a postdoctoral institution with a strong cancer research program that will enable me to pursue a new, complementary avenue of training in the design and fabrication of personalized multifunctional nanoparticle-based vaccine systems. The two phases of this award will align to provide the foundation for establishment of an independent cancer research lab predicated on the use of therapeutic ultrasound and multifunctional nanoparticles as a platform for personalized cancer vaccination. The combination of these research areas significantly caters to the academic training, research experiences, and unique perspectives offered by my background as a biomedical engineer.